Immuno: Autoinflammatory and Autoimmune diseases 1 Flashcards
What is the difference between autoinflammatory and autoimmune disease?
Autoinflammatory = driven by components of the innate immune system
- Not characterised by autoantibodies and HLA associations are usually less strong
Autoimmune = driven by components of the adaptive immune system
- Autoantibodies are found and HLA associations are common
(Breaking of tolerance - aberrant T and B cell response in 1 and 2 lymphoid organs)
Note: mixed pattern diseases involve mutations affecting the innate and adaptive immune system → HLA associations may be present but autoantibodies are NOT usually a feature
Which cells are mainly responsible for:
- Autoinflammatory diseases
- Autoimmune diseases
- Autoinflammatory diseases = macrophages and neutrophils (disease is usually localised)
- Autoimmune diseases = T and B cells
Inherited DNA sequence is not the only factor affecting protein expression, what are the other factors?
- Genetics – Germline mutations affecting DNA sequence - Alteration in DNA that occurs in germ cells (sperm and ova and progenitors) and will be passed on to offspring
- Genetics – Somatic mutations affecting DNA sequence - Alteration in DNA that occurs in a single body cell after conception, does not affect germ cells and so is not inherited
- Epigenetics - (Heritable) change in gene expression
(eg via DNA methylation) - MicroRNA (miRNA) - Small, non-coding, single stranded RNA
targets mRNA and regulate protein production
List examples of monogenic autoinflammatory diseases
Familial Mediterranean Fever
TRAPS
List examples of polygenic autoinflammatory diseases
Crohn’s
UC
Osteoarthritis
Giant cell arteritis
Takayasu’s
List examples of monogenic autoimmune diseases
APECED
IPEX
ALPS
List examples of polygenic autoimmune diseases
Rheumatoid arthritis
Myasthenia
Pernicious anaemia
Graves disease
List examples of mixed pattern diseases
Ankylosing spondylitis
Psoriatic arthritis
Behcet’s
Mutations in which pathways are implicated in monogenic autoinflammatory disease?
Innate immune cell function - abnormal signalling via key cytokine pathways involving TNF-alpha or IL-1
Which protein is upregulated in autoinflammatory diseases caused by gain-of-function mutation in NLRP3?
Cryopyrin (aka NLRP3)
Name 3 diseases that are caused by mutation of NLRP3?
- Muckle Wells syndrome
- Familial cold autoinflammatory syndrome
- Chronic infantile neurological cutaneous articular syndrome/Neonatal Onset Multisystem inflammatory disorder (NOMID)
- These are all autosomal dominant
NOTE: other examples of monogenic autoinflammatory conditions: TNF receptor associated periodic syndrome (TNF receptor mutation), Hyper IgD with periodic fever syndrome (mevalonate kinase mutation)
Which gene mutation causes Familial Mediterranean Fever and which protein does this gene encode?
MEFV gene
Encodes pyrin-marenostrin which is ordinarily a negative regulator of the inflammatory pathway → mutation leads to increased inflammation
Describe how the inflammasome complex functions.
- The pathway is activated by toxins, pathogens and urate crystals
- These act via cyropyrin and ASC (apoptosis-associated speck-like protein) to activate procaspin 1
- Activation of procaspin 1 results in the production of NFkB, IL-1 and apoptosis
- Pyrin-marenostrin is a negative regulator of this pathway
Which mutations can lead to hyperactivity of the inflammasome complex?
- Loss of function of pyrin-marenostrin
- Gain of function of cryopyrin
What is the inheritance pattern of Familial Mediterranean Fever?
Autosomal recessive
Which cells contain pyrin-maronostrin?
Neutrophils
Outline the clinical presentation of Familial Mediterranean Fever.
Periodic fevers lasting 2-4 days associated with:
- Abdominal pain (peritonitis)
- Chest pain (pleurisy, pericarditis)
- Arthritis
- Rash
What is a complication of Familial Mediterranean Fever?
AA amyloidosis
(due to chronic elevation of serum amyloid A)
This can deposit in the kidneys causing nephrotic syndome and renal failure
What are the investigations of Familial Mediterranean Fever?
- High CRP, high Serum Amyloid A (SAA)
- Blood sample to specialist genetics laboratory to identify MEFV mutation
Outline the treatment of Familial Mediterranean Fever.
- Colchicine 500µg BD (binds to tubulin and disrupts neutrophil migration and chemokine secretion)
- 2nd line: blocking cytokines
- Anakinra - IL-1 receptor blocker
- Etanercept - TNF-alpha blocker
What are two types of pathogenesis in monogenic autoimmune diseases?
Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function
- Abnormality in regulatory T cells (IPEX)
- Abnormality of lymphocyte apoptosis (ALPS)
What does IPEX stand for?
Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome
What mutation causes IPEX? What is the role of this gene?
FoxP3 - required for the development of Treg cells
A lack of Tregs leads to autoantibody formation
- Failure to negatively regulate T cell responses
- Autoreactive B cells -> limited repertoire of autoreactive B cells
Which autoimmune conditions are often seen in IPEX?
“Diabetes, dermatitis, Diarrhoea”
* Enteropathy
* Diabetes mellitus
* Hypothyroidism
* Dermatitis (Eczema)
What does ALPS stand for?
Autoimmune lymphoproliferative syndrome
Which mutations cause ALPS?
Mutations in the FAS pathway leading to defects in apoptosis of lymphocytes
This leads to a failure of lymphocyte tolerance (as autoreactive lymphocytes don’t die by apoptosis) and failure of lymphocyte homeostasis (you keep producing lymphocytes)
Describe the clinical phenotype of ALPS.
- High lymphocyte count
- Large spleen and lymph nodes
- Autoimmune disease (usually cytopaenias)
- Lymphoma - over time
What is the best known chromosomal region that is implicated in Crohn’s disease?
IBD1 on chromosome 16
Which gene in this region is associated with Crohn’s disease?
(Chromosome 16)
NOD2 (aka CARD15)
Abnormalities are associated with increased risk of Crohn’s, Blau syndrome and some forms of sarcoidosis
Where is NOD2 found and what is its role?
Cytoplasm of myeloid cells
Acts as a microbial sensor
(recognises muramyl dipeptide)
Outline the treatment approaches to Crohn’s disease
- Corticosteroids
- Azathioprine
- Anti-TNF-alpha antibodies
- Anti-IL 12/23 antibodies
What is the strongest genetic association of ankylosing spondylitis?
HLA-B27
NOTE: othes include IL23R, ERAP1, ANTXR2 and ILR2
90% heritability
Where does ankylosing spondylitis tend to manifest?
At sites with high shear forces (i.e. entheses, SI Joint)
What are the treatment options for ankylosing spondylitis?
- NSAIDs
- Immunosuppression (anti-TNF-alpha and anti-IL17)
List the autoimmune diseases associated with the following HLA polymorphisms:
- DR3
- DR3/4
- DR4
- DR15
- DR3
- Graves’ disease
- SLE
- DR3/4
- Type 1 diabetes mellitus
- DR4
- Rheumatoid arthritis
- DR15
- Goodpasture’s syndrome
Name and state the function of 2 genes that are involved in T cell activation and are often mutated in polygenic autoimmune disease.
- PTPN22 - suppresses T cell activation
- CTLA4 - regulates T cell function (expressed by T cells)
What are three forms of peripheral tolerance?
- T cell require costimulation to become activated (costimulatory molecules are upregulated in infection and inflammation)
- Regulatory T cells
- Immune privileged sites
Outline the Gel and Coombs effector mechanisms of immunopathology.
Type I: Anaphylactic hypersensitivity - immediate hypersensitivity which is IgE-mediated
Type II: Cytotoxic hypersensitivity - antibody reacts with cellular antigen
Type III: Immune complex hypersensitivity - antibody reacts with soluble antigen to form an immune complex
Type IV: Delayed-type hypersensitivity - T cell mediated response
NOTE: autoimmunity is most common with type II hypersensitivity
Effect of Type II Hypersensitivity
- Activate complement
- Activate NK cells
- Opsonin for phagocytosis
List some inflammatory mediates involved in type I responses that are:
- Pre-formed
- Synthesised
- Pre-formed: Histamine, Serotonin, Proteases
- Synthesised: Leukotrienes, prostaglandins, bradykinin, cytokines
Outline the pathophysiology of IgE-mediated type I responses.
IgE binds to a foreign antigen (e.g. pollen)
The Fc portion binds to mast cells and basophils leading to degranulation
NOTE: this mechanism is implicated in eczema
How does antibodies binding to cellular antigens lead to cell death?
Antibody-dependent cellular cytotoxicity:
antibodies can activate complement (by binding to C1) or bind to NK cells and macrophages resulting in phagocytosis
What is sometimes considered a type V hypersensitivity reaction?
Antibodies activate or block cellular receptors (e.g. Graves’ disease, myasthenia gravis)
Name the autoantigen in the following diseases:
- Goodpasture’s disease
- Pemphigus vulgaris
- Graves’ disease
- Myasthennia gravis
- Goodpasture’s disease = non-collagenous domain of basement membrane collagen IV
- Pemphigus vulgaris = Epidermal cadherin
- Graves’ disease = TSH receptor
- Myasthenia gravis = nicotinic acetylcholine receptor
What are the consequences of immune complex formation in type III hypersensitivity reactions?
Immune complexes can deposit in blood vessels
(especially in the kidneys (nephritis), joints and skin (purpura)
They activate complement and inflammatory cells through their Fc portion
Classic example - SLE
What is the autoantigen in:
- SLE
- Rheumatoid arthritis
- SLE: DNA, histones, RNP
- Rheumatoid arthritis: Fc portion of IgG
Give some examples of type IV hypersensitivity mediated diseases and state the autoantigen involved.
- Insulin-dependent diabetes mellitus: pancreatic beta-cell antigen
- Multiple sclerosis: myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein
In Type IV hypersensitivity reactions in autoimmunity, what HLA do CD8 and CD4 T cells bind to?
HLA class I molecules present antigen to CD8 T cells
HLA class II molecules present antigen to CD4 T cells
